Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
  • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
  • B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
  • B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
  • B01J23/44—Palladium
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
  • C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
  • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/40—Oxygen atoms
  • C07D211/44—Oxygen atoms attached in position 4
  • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
  • C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/12—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by hydrolysis, i.e. solvolysis in general
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• the present invention relates to a reagent and a method useful for cleaving a protected function, on the occasion of an organic synthesis by an allyl group, from this one.
• protection techniques are mainly used for the synthesis of complex molecules such as peptides of at least 2 amino acids more often of at least three, or when complex amino acids are used, ie those which have a mobile hydrogen function (amine, alcohol including phenol, nitrogen cycle, thiol, . «) in addition to an acid function and in addition to an amino function. They are also useful for nucleotides, nucleosides, polynucleotides and polynucleosides.
• a protecting group can also be useful for molecules having at least six carbon atoms, advantageously twelve, or for molecules which have several functions at least two, advantageously three functions.
• the only protective groups of the allyl type which are used are the allyloxycarbonyl groups, the release of which has been treated in previous applications (in particular the application filed in France under No. 92/044621 and the corresponding European application) of the Applicant and which are not to be confused with the allylated derivatives according to the present application; these allyloxycarbonyl derivatives have a carbonyl function derived from an acid function which makes cleavage less difficult.
• the deprotection usually used is lysis in an acid medium, in general in an anhydrous halohydric medium (that is to say with a water content in general less than 1%, advantageously at 10 -3 , preferably at 10 -4 ) .
• one of the aims of the present invention is to provide a process and a reagent which allow the cleavage of an allylic protecting group with the function which it protects.
• Another object of the present invention is to provide a process and a reagent which avoid alkylation reactions of aromatic rings.
• Another object of the present invention is to provide a method and a reagent which avoid the alkylation reactions of function (s) belonging to the same molecule and qualified (s) as nucleophile.
• the reagent according to the present invention comprises:
• a catalyst comprising at least one element from column VIII of the periodic table, said element from column VIII of the periodic table being coordinated by at least one coordinating agent soluble in said solvent system (s);
• the solvent system can be single-phase or two-phase (i.e. with an aqueous liquid phase and an organic phase).
• Solvents A are organic solvents chosen so that they dissolve at least 1%, advantageously at least 2%, preferably 5% by mass of the substrate and are sufficiently hydrophobic not to be miscible with water in any proportion .
• A advantageously at most 1%, by mass, even in the presence of the substrate as a third solvent.
• the solvent A can only dissolve at most 10% water, advantageously at most 1%, by mass, even in the presence of the substrate as a third solvent.
• Solvents A can be mixtures, including petroleum fractions. Naturally, under the operating conditions the solvents A must be inert with respect to the substrates and the reagents used.
• phase transfer agents can be added which will be distributed between the two phases.
• the preferred families of solvents are chosen from the group consisting of hydrocarbons, aromatic derivatives, ethers, esters and halogenated solvents. If it is desired to recover these solvents it is desirable that they be less nucleophilic than said nucleophilic compound, so as not to interfere with the reaction unless, of course, said nucleophilic compound is in excess sufficient to play a role of ( third) solvent.
• the solvent A is distillable under atmospheric pressure or under primary or secondary vacuum.
• This third solvent B can be divided between aqueous and organic phases when the latter exists, either initially, or due to the possible simultaneous use of solvent A.
• the water can dissolve at least 1/10 of third solvent B, advantageously at least 1/3, by mass, even in the presence of the catalyst with its coordinating agents.
• the third solvent is added in an amount sufficient for the amount of substrate soluble in the aqueous phase to be at least of the same order of magnitude as the amount of catalyst present in the aqueous phase at the start of the reaction.
• the solvents which are used as a third solvent in the case of the two-phase system can be used.
• solvents which can be used as solvent or third-party solvent mention may be made of water-soluble solvents of the alcohol, nitrile, ether (especially cyclic), acid, sulfone, sulfoxide, simple or polyfunctional amide (like urea), ester, ketone, or even amine in particular in the case where said nucleophilic compound also serves as a (third) solvent.
• a system of solvent (s), monophasic or not, comprising a hydrophilic phase that is to say comprising as principal constituent a solvent, or a mixture of solvent, miscible in any proportion and itself miscible in large proportions.
• the metals giving the best catalytic results are the metals of the platinum mine, preferably those which are either isoelectronic of palladium, or else in a valence state which is isoelectronic of zero palladium, preferably both; however, it may be economically advantageous to use lighter metals because of their much lower cost; within the family of metals of the platinum mine, each of them presents specificities which make them more or less interesting depending on the case; palladium, especially in the zero oxidation state, most often gives the best results.
• said coordinating agents are trivalent hydrocarbon derivatives of the elements of column VB, advantageously of period of a rank greater than the second and in general less than the sixth, of the periodic classification of the elements (supplement to the Bulletin of the Chemical Society from France January 1966 N ° 1).
• examples of such compounds may be given the derivatives of trivalent oxygenated acids (phosphorous, arsenious, antimonious and, for the record, nitrous) derivatives obtained in particular by esterification or by substitution of at most two of the three oxhydryls ( trisubstitution actually leads to pnictines which is the subject of a more detailed description).
• hydrocarbon derivatives of the elements of column V the preferred are those which derive from hydrogen pnictures by total or partial substitution of hydrogen by hydrocarbon residues which can be linked to the atom of column VB by a double (as in imines) or a triple bond (as in nitriles).
• the hydrocarbon derivatives of the elements of column V are advantageously derived from hydrogen pnictures by total or partial substitution of hydrogen by monovalent hydrocarbon residues advantageously by alkyls [in the present description ALCO-yl is taken in its. etymological sense of the hydrocarbon residue of an ALCO-ol after ignorance of the alcohol (or ol) function]; these alkyl compounds will, by analogy with the term pnicture, designated in the present description, under the term of pnictines.
• said catalyst comprises, as water-soluble coordinating agent, a pnictine, a trialkoyphosphine, preferably (for economic reasons) a triarylphosphine, in general a triphenylphosphine.
• Said phosphine and said metal from column VIII are advantageously in the form of tetrakis phosphine metal.
• graft neutral groups such as polyols
• graft neutral groups such as polyols
• the grafted groups be ionic, cationic such as quaternary ammoniums or anionic, like any group constituting the associated base of the acids preferably strong.
• triphenyiphosphinetrisuifonates P (C 6 H 4 -SO 3 -) 3 solubies, for example alkalies and those of formula P (C 6 H 4 -CO 2 H) 3 , preferably under anionic form.
• a two-phase system can be used in which one of the
• 2 liquid phases is an aqueous phase, in which the metal of column VIII is dissolved in the aqueous phase by a pnictine, or equivalent, water-soluble.
• phosphines with a high basicity generally phosphines with a high basicity
• ⁇ or polyfunctional pnictins generally bifunctional, allowing a cheatiation of the metal by the pnictine functions; in general the pnictine functions are, taking the most direct path, separated by 2, 3 or 4 atoms, most often of carbon; the formulas of type ⁇ , ⁇ 'diphenylphosphinoethane; or ⁇ , ⁇ 'diphenylphosphinobutane.
• the two-phase technique greatly facilitates the recovery and recycling of the catalyst, which recycling is one of the key parameters of the profitability of this type of process due to the ever increasing price of metals from the platinum mine.
• a metal catalyst can be used in elementary form (zero oxidation state) or in oxidized form. These catalysts can be in the form of salts, oxides or complexes.
• salts, oxides and complexes of the metals mentioned above in the oxidation state II, there may be mentioned palladium chlorides, palladium acetate, palladium chloride complexed with benzonitrile. It should be emphasized that anions are of small importance, only cations count.
• an amount of catalyst such as the molar ratio between the metal catalyst and the compounds of the elements of column V, when the latter compounds are in the form of coordinating agents, too often designated by the Anglo-Saxon expression of Ligand, that is to say between 2 and 100, more generally from 4 to 30.
• These molar ratios must take account of the number of coordinating functions per molecule; thus, when molecules having two pnictin functions are used as coordinating agent, the values of the above domains should be halved.
• the amount of solvent system (s) used is such that the concentration of the metal of column VIII is preferably greater than 10 -5 , advantageously from 10 -2 to 10 -3 M in the solvent.
• nucleophilic compound must have two characteristics; on the one hand it must be nucleophilic, that is to say rich in electrons and on the other hand be soluble in the system of solvent (s).
• nucl ⁇ ophilies have at least equal to that of diethylamine (see "March” 3rd edition pp 307309)
• nucleophile depends on the functions to be deprotected in general, it is preferred to use as nucleophiles, molecules carrying function (s) at least as nucleophilic (s) as the functions vis-à-vis which it is necessary to be selective.
• the functions whose alkylation is to be avoided are protonated and a non-protonatable nucleophile is chosen under the operating conditions.
• the above constraint on the nucleophilic character becomes that the nucleophilia must be greater than that of the NH4 + ion -
• This protonation takes place in the aqueous phase using acid whose pKa is at least 1 point lower , preferably at least 2 points at the pKa of the acid associated with the nucleophilic function that it is desired to protect.
• An excess of at least 10% over the amount necessary for neutralization is preferable
• nucleophilic functions are preferably those in which at least one mesomeric formula carries a hydrogen; They can be anions or neutral molecules.
• divalent sulfur such as thiol, or polysulphide, thioacids
• carbanions for example malonic or ⁇ -diketonic function
• phosphines, amines, anilines phosphines, amines, anilines .
• Certain functions such as primary pnictins, or as molecules of malonic type such as betadiketones can serve several (usually two as in the case of the examples above) times of nucleophiles and this fact must be taken into account for the calculation of the stoichiometric quantity.
• the preferred nucleophilic functions are those which correspond to atoms of a line of the periodic table at least equal to the third such as sulfur, for example of the hydrogen sulfide function.
• the function to be desaliylated is a base of the pnictin type
• the substrate does not have an adequate acid function
• an acid whose pka demonstrates an acidity of at least one unit, preferably at least two units, greater than the acidity of the acid associated with said base, it is preferable that at least 50%, more advantageously 90% of said base is in protonated form.
• the acid can be provided by the same molecule as the nucleophile, as mentioned below.
• nucleophilic compound When it is desired, to be hydrophilic, or rather water-soluble, that is to say that it is soluble in water, said nucleophilic compound must be such that under normal conditions water is capable of dissolving at least 0.2 advantageously 0.5 preferably 1 gram equivalent of nucleophilic function.
• hydrophilic nucleophilic reagents which are not or little so providing for a highly hydrophilic function on the molecule.
• Strong or medium acid functions (pKa at most equal to 6, advantageously 5, preferably 4), whether they are sulphurized (sulphonic, sulfuric monoester, etc.), phosphorous (phosphoric ester, phosphonic acid, phosphinic acid, ....), carbonaceous, or others, give results good enough that one wonders if there is no synergy. The best results are obtained to date with a carbon function, namely the carboxylic function.
• nucleophiles where the nucleophilic function is carried by a postvicinal or preferably vicinal carbon of that carrying the acid function.
• the atom carrying acid hydrogen (or one of the atoms carrying acid hydrogen if there is more than one acid function) and the nucleophilic atom, and including these two atoms, it has, by the shortest path, a number of links between 3 and 7, preferably between 4 and 6.
• thiosalicylic acid (HS ⁇ - COOH) (number of links equal to 5), in particular in monoanionic or, preferably acid, form.
• the best results are those obtained by the association of nucleophilic functions which are not or hardly protonatable with the acid functions. The results obtained with zwitt ⁇ iones are sometimes mediocre.
• the water and the nucleophile are miscible in any proportion.
• the same compound can carry several nucleophilic functions
• nucleophilic function for 10 carbon atoms, advantageously one for 8, preferably one for 4.
• nucleophilic compound which sees its solubility decrease considerably with temperature in order to pass into the gas phase, thus allowing easy movement by distillation.
• said nucleophilic compound is present (initially but more preferably at the end of the reaction) at a concentration of at least 1/2, advantageously 2, preferably 5 gram equivalent per liter.
• nucleophilic compound When the nucleophilic compound presents, reduced to a nucleophilic function a low molecular mass, concentrations as high as 10 equivalents per gram are often exceeded.
• the desallylation provided by the use of the aqueous phase is not considered sufficient and it is desired to increase it, this can be done to act on the excess of said nucleophilic compound relative to the substrate, for example by increasing the stoichiometric excess (in general much greater than 10%) relative to the desired reaction to bring it to a value at least equal to 1/4, advantageously to 1/2 preferably once to the stoichiometric amount (c ' i.e. work with quantities respectively at least equal to 5/4; 3/2 and 2 QS).
• the amount of said nucleophile is at least equal to 3/2 times the stoichiometrically necessary amount.
• such stoichiometric excesses are only used when a total desallylation is desired.
• Another object of the present invention is to provide a process which substantially accelerates the kinetics of cleavage.
• Another object of the present invention is to provide a process which avoids alkylation reactions of aromatic rings.
• Another object of the present invention is to provide a process which avoids the reactions of alkylation of the functions called nucleophile.
• said molecules comprise at least one allyl function corresponding to the following formula (l):
• R 1 represents a hydrogen or an alkyl radical, preferably with 1 or 2 carbon atoms
• R 2 represents a hydrogen or an alkyl radical, preferably with 1 or 2 carbon atoms
• R 3 represents a hydrogen or an alkyl radical, preferably with 1 or 2 carbon atoms, or, with R 4 forms an additional double bond;
• R 4 represents a hydrogen or an alkyl radical, preferably with 1 or 2 carbon atoms or, with R3 forms an additional double bond;
• R 5 represents a hydrogen or an alkyl radical, preferably with 1 or 2 carbon atoms or aryl;
• Z being the radical resulting from the molecule to protect the bond replacing a hydrogen of the function whose protection is desired.
• Z contains the protected molecule which must be released from its protective group;
• Z can of course have one or more allyl ester functions, but elsewhere in the molecule.
• Rg Said function to be protected not being an acid or equivalent function Rg may be a group called "Ar” as described in the British patent application filed on 12.31.1990 under No. 90 28208.8 and entitled "Protective group"
• R 5 and R 4 may be fractions of the group called "Ar" in the above application so that R 5 and R 4 as well as the carbon which carries them forms an Ar radical as defined in the British application above.
• R 5 can be any lipophilic group as described in the French patent applications in the name of the applicant filed on 02.10.1989 under the number N ° 89/13054 and entitled “Process for the solubilization of peptides and process for the synthesis of peptides.” and that deposited on 12.4.1989 under N ° 89/15957 and entitled “Reaction medium and solubilizer of peptides and synthesis process using this medium.”
• the association of the group designated by Ar in the British application above with an allyl group as "L" is very favorable.
• Z is of structure Z'-X- with X being an atom of columns V or VI, advantageously V, preferably a nitrogen (itself advantageously alkylated so that in the final formula nitrogen is tertiary, if we want to facilitate the cleavage).
• Z 'advantageously has no carbonyl function linked to X
• alkyl is taken in its etymological sense already specified with the additional precision that it can also mean an aryl group.
• radicals R1 to R5 are at most two carbons; however, at least one of the radicals R1 to R5 can be such that the allyl alcohol is a heavy alcohol, for example of aromatic series, of terpene type or of steroid series.
• At least 1 radical and at most 3 radicals R1 to R5 can be polycyclic aryl radicals, condensed or not, homo or heterocyclic.
• the allyl i being such that there are advantageously in the molecule at least two, preferably 3, different formulas from allyl i . It is preferable that these formulas respectively have 0, 1 and / or 2 substituents R 1 to R 5 .
• N is advantageously at least equal to two preferably to 3 and n is generally at most equal to 10 (a significant figure)
• the reaction temperature is generally between the ending melting point and the starting boiling point of the reaction medium.
• 0 ° C and 100 ° C preferably between the ambient (about 20 ° C) and 50 ° C.
• direct allylated derivatives (direct as opposed to allyloxycarbonyl derivatives where it is possible for example to use the amino function are protected in the form of an allyloxycarbamate, the breakdown of the ester function inducing that of the carbamic function, liberating ipso facto the amino function), i.e. having no carbonyl function in post homoallylic position facilitating cleavage (as for example in the case of allyl carboxylates), to protect various functions having a mobile hydrogen.
• a primary amino function can be protected by means of two allyl functions.
• ⁇ preferably use only the only stoichiometric quantity (more or less 10%) necessary for the first desallylation
• the method according to the invention respects the geometry of the molecules and is therefore particularly well suited to the chemistry of chiral molecules.
• the catalyst is preformed with stirring for 15 minutes, under argon, the Pd (dba) 2 and the coordinator diphenylphosphinobutane (DPPB) (1: 1) in 1 ml of anhydrous THF (2.5 to 5% of catalyst for the reaction). We then obtain a reddish-brown solution.
• the reaction medium is filtered through silica gel (eluent: AcOEt / cyclohexane (1: 1). The filtrate is then concentrated under reduced pressure.
• the nucleophile is mercapto-2-benzoic acid
• the latter can be separated from the deprotected product by treatment with a basic solution (10% NaOH) during an extraction with ethyl acetate.
• the organic phase is dried and then concentrated.
• the deprotected products can be purified by chromatography on silica gel or distilled.

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• 1993
  • 1993-04-09 FR FR9304233A patent/FR2703688B1/fr not_active Expired - Lifetime
• 1994
  • 1994-04-08 HU HU9502942A patent/HU218397B/hu not_active IP Right Cessation
  • 1994-04-08 AU AU65410/94A patent/AU697811B2/en not_active Ceased
  • 1994-04-08 CN CNB941920429A patent/CN1160308C/zh not_active Expired - Fee Related
  • 1994-04-08 KR KR1019950704413A patent/KR100340613B1/ko not_active IP Right Cessation
  • 1994-04-08 US US08/532,630 patent/US5773617A/en not_active Expired - Fee Related
  • 1994-04-08 BR BR9406137A patent/BR9406137A/pt not_active IP Right Cessation
  • 1994-04-08 ES ES94913152T patent/ES2166372T3/es not_active Expired - Lifetime
  • 1994-04-08 AT AT94913152T patent/ATE211725T1/de not_active IP Right Cessation
  • 1994-04-08 WO PCT/FR1994/000397 patent/WO1994024088A1/fr active IP Right Grant
  • 1994-04-08 EP EP94913152A patent/EP0693052B1/de not_active Expired - Lifetime
  • 1994-04-08 CA CA002160163A patent/CA2160163A1/fr not_active Abandoned
  • 1994-04-08 JP JP52282094A patent/JP3657605B2/ja not_active Expired - Fee Related
  • 1994-04-08 DE DE69429616T patent/DE69429616T2/de not_active Expired - Fee Related
• 1995
  • 1995-10-06 NO NO953976A patent/NO953976L/no unknown
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